The principal investigator is seeking advanced training in neurophysiology, neurotransmitter pharmacology, and signal transduction in the field of pain research to become an independent clinician-scientist. The career development award will provide funding and time-protection to conduct research on pain pathways, specifically the role of norepinephrine transporters (NET) in nociceptive/antinociceptive signaling in spinal cord. Studies will also be performed to demonstrate whether there is an interaction between opioid receptor and NET in the spinal cord and the potential effect of cocaine, a psychostirnulant that interact with NET, on pain processing. These studies will lead us to better understand the mechanisms of signaling among the neurotransmitters and receptors in the spinal cord pain processing. Using a combination of behavioral physiological studies, biochemical and modem molecular biological techniques, the principal investigator proposes to use rats and PC 12 cells to study spinal cord NET expression, function, signaling and its role in nociceptive/antinociceptive processing. The specific aims of the proposed studies are: 1: To elucidate the role of NET in the modulation of the analgesic response to opioids. 2: To examine the protein localization, expression and function of NET in the spinal cord using immnuohistochemistry, immunoblotting and NE uptake assay, respectively. 3: To examine the biochemical basis for the synergistic interaction between alpha2-adrenergic and mu-opioid receptor agonists. 4: To examine for a possible reciprocal regulation of NET protein trafficking by mu-opioid receptor activation. As an anesthesiologist, the principal investigator is involved in the management of pain in patients during the perioperative period. Her practice in the urban setting often necessitates providing care for patients who may have acute exposure to cocaine. The proposed studies will enhance the understanding of the mechanism of spinal cord nociceptive/antinociceptive signaling, and the specific role of NET and cocaine which regulates NET function. The studies will provide important information on the role of spinal cord NET in nociceptive/antinociceptive signaling and may enhance our ability to use psychostimulants in the management fo pain. The findings from these studies could potentially be translated into development of novel therapeutic targets in pain management and strategies of pain management in the cocaine abusing patient.